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Alternative titles; symbolsCDG2UMENTAL RETARDATION, AUTOSOMAL RECESSIVE 15, FORMERLY; MRT15, FORMERLY▼ DescriptionRafiq syndrome (RAFQS) is an autosomal recessiv...

Alternative titles; symbols

  • CDG2U

▼ Description

Rafiq syndrome (RAFQS) is an autosomal recessive disorder characterized by variably impaired intellectual and motor development, a characteristic facial dysmorphism, truncal obesity, and hypotonia. The facial dysmorphism comprises prominent eyebrows with lateral thinning, downward-slanting palpebral fissures, bulbous tip of the nose, large ears, and a thin upper lip. Behavioral problems, including overeating, verbal and physical aggression, have been reported in some cases. Serum transferrin isoelectric focusing shows a type 2 pattern (summary by Balasubramanian et al., 2019).

▼ Clinical Features

Rafiq et al. (2010) reported 3 consanguineous Pakistani families in which patients had severely impaired intellectual development, all but 1 with an IQ less than 40 and all with delayed speech. Two of 3 sibs in 1 family had truncal obesity, and 2 other patients had epilepsy. None had microcephaly or autistic features. The families belonged to the same clan and were from the same village. Rafiq et al. (2011) provided follow-up of these families, which were from the Punjab province. Two patients had delayed psychomotor development and began walking at age 4 years. Both had hyperphagia and were overweight. Some patients achieved speaking in sentences and toilet training; aggression was a common feature. Mild dysmorphic features, such as dolichocephaly, downslanted palpebral fissures, broad nose, and small chin, were noted.

Rafiq et al. (2011) reported another consanguineous Pakistani family from the Sindh province with a similar, but less severe, form of impaired intellectual development. In addition to impaired intellectual development, these patients showed dysmorphic features, including downslanting palpebral fissures, hypertelorism, long face, flattened malar region, short philtrum, broad nasal root, and small chin. Rafiq et al. (2011) also described 3 members of an Iranian family with variably impaired intellectual development, with 1 patient able to speak and count money and the others more severely affected. Seizures were variable. Dysmorphic features were mild and variable, but included dolichocephaly, long face, flat philtrum, downslanting palpebral fissures, hypertelorism, thin upper lip, triangular and pointed chin, and prominent nose.

Rymen et al. (2013) reported 7 patients from 6 families with Rafiq syndrome. All of the patients, who ranged in age from 11 to 24 years, had mildly to severely impaired intellectual development, hypotonia, truncal obesity, delayed motor development, and facial dysmorphisms, including downslanting palpebral fissures, large and low-set ears, and a thin upper lip. Hypertelorism was present in 6 patients, skin laxity in 5, joint hypermobility in 4, and inverted nipples in 4. One patient (P5) had seizures. Brain MRI findings included multiple small white matter lesions in 1 patient (P6) and cerebellar hypoplasia with vermian atrophy in another (P1). Rymen et al. (2013) stated that the disorder was a congenital disorder of glycosylation.

Van Scherpenzeel et al. (2014) reported 12 patients (including 3 sib pairs) from 9 families with Rafiq syndrome. All 12 patients, who ranged in age from 3 to 35 years, had global developmental delay including speech and motor delay. All 9 patients older than 5 years were diagnosed with impaired intellectual development, ranging from mild/moderate to severe. Eight of 12 patients had hypotonia, 5 had strabismus, 3 had seizures, 3 had aggression, and 2 had ataxia. Eleven of 12 patients had dysmorphic features, including 7 with thin lateral eyebrows, 7 with a bulbous nasal tip, 6 with a thin upper lip, 5 with inverted nipples, and 5 with abnormal fat distribution. Eight patients had macrocephaly, 3 had dolichocephaly, and 3 had joint laxity. Eight patients had truncal obesity and 5 were overweight based on BMI. Mildly abnormal liver function, including decreased antithrombin III, elevated APTT, elevated PT, and mildly elevated transaminases, were reported in 2 patients.

Balasubramanian et al. (2019) reported 2 sib pairs from unrelated European families with Rafiq Syndrome, which they called MAN1B1-CDG. The patients had a type 2 pattern on serum transferrin isoelectric focusing. All 4 of the patients had facial dysmorphisms, developmental delay, hypotonia, and impaired intellectual development. Three of them had truncal obesity, and 2 had behavioral issues. A brain MRI of one of the patients at age 2 years showed bilateral ventricular heterotopia with overlying cortical dysplasia.

▼ Biochemical Features

Van Scherpenzeel et al. (2014) reported that 12 patients with Rafiq syndrome had a recognizable pattern of an isolated increase in trisialotransferrin on routine transferrin isoelectric focusing. Isoelectric focusing of APOC3 (107720) did not show abnormalities. Van Scherpenzeel et al. (2014) developed a high resolution mass spectrometry method to analyze the glycoprofile of intact plasma transferrin, which allowed for discrimination of major normal and abnormal glycans. This assay identified a characteristic glycosylation signature with abnormal hybrid-type N-glycans. Hybrid-type N-glycans were also detected in alpha-1-antitrypsin and IgG in patient serum.

▼ Inheritance

The transmission pattern of RAFQS in the families reported by Rafiq et al. (2010) was consistent with autosomal recessive inheritance.

▼ Mapping

By homozygosity mapping of 3 consanguineous Pakistani families with RAFQS, Rafiq et al. (2010) identified a locus for the disorder on chromosome 9q34.4 (lod score of 4.8).

By homozygosity mapping of 2 consanguineous Iranian families with mildly to moderately impaired intellectual development (families 8600060 and G015), Kuss et al. (2011) found linkage to a 2.5-Mb region on 9q34.3 (lod score of 3.1 and 3.3, respectively).

▼ Molecular Genetics

In affected members of 5 families with RAFQS, Rafiq et al. (2011) identified 3 different homozygous mutations in the MAN1B1 gene (604346.0001-604346.0003).

Rymen et al. (2013) reported 7 patients from 6 families with Rafiq syndrome and biallelic mutations in the MAN1B1 gene. A homozygous mutation (S409P; 604346.0004) in the first patient was identified by whole-exome sequencing. The other mutations (604346.0003-604346.0008) were identified by direct gene sequencing in patients with a type 2 pattern on transferrin isoelectric focusing.

Van Scherpenzeel et al. (2014) reported 12 patients (including 3 sib pairs) from 9 families with Rafiq syndrome and biallelic mutations in MAN1B1 (see, e.g., 604346.0003; 604346.0009-604346.0010). The first mutation was found by whole-exome sequencing and the other mutations by Sanger sequencing in patients who were found to have abnormal, hybrid-type glycoproteins on high resolution mass spectrometry. The mutations included 6 missense, 4 nonsense, 2 frameshift, 1 splicing, and 1 deletion.

In 3 Turkish sibs, born to consanguineous parents, with Rafiq syndrome, Hoffjan et al. (2015) identified homozygosity for a recurrent missense mutation in the MAN1B1 gene (R334C; 604346.0003). The mutation, which was identified by autozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family.

By whole-exome sequencing in 2 sib pairs from unrelated European families with Rafiq syndrome, Balasubramanian et al. (2019) identified homozygous (604346.0012) or compound heterozygous (604346.0003; 604346.0011) mutations in the MAN1B1 gene, respectively. The patients had a type 2 pattern on serum transferrin isoelectric focusing. The mutations segregated with the phenotype in both families.

Tags: 9q34.3